We aim to probe the structural features of the G-protein coupled receptors (PTH1 and PTH2) for parathyroid hormone (PTH). PTH is one of the few bone-active agents proven to be anabolic in humans and therefore has been intensively examined as a possible target for the treatment of osteoporosis. We aim to characterize, on a structural basis, the association of the receptor to the G-proteins (Gs and Gq) known to couple to it. Additionally, the association of PTH1 to beta-arrestin2, an important step in the internalization of the receptor will also be structurally examined. A second aim is to utilize the structural features of PTH and PTH1 previously determined in our group to rationally design low molecular weight PTH-based analogs. It is well established that the N-terminus of PTH is responsible for receptor activation. However, this domain alone, PTH(1-14), has extremely low binding affinity. Through random screening, analogs with low uM potencies (e.g., (Ala3, 10,12, Arg11)PTH(1-14)) have been developed. Our structural characterization of this lead compound has provided a number of methods to incorporate additional conformational constraint (cyclization) as well as non-natural amino acids and peptidomimetics. The research described here will facilitate the rational design and optimization of PTH-based agents for the regulation of calcium homeostasis. A final aim is to utilize the establishment of the pharmacophore for the PTH1 receptor, as well as structural characterization of TIP39 (tuberoinfundibular peptide-39) to develop a structure-activity relationship for the PTH2 receptor. Such information would facilitate the design of stable, PTH2 specific antagonist, which would assist in the establishing the physiological role of the receptor, thought to be involved in release of pituitary and pancreatic hormones and possibly perception of pain. Given that PTH activates both receptors, and TIP39(7-39) is specific for PTH1, there is a great synergy between the latter two aims; the results aimed to develop a valuable tool for the physiological characterization of PTH2 will accelerate the rational design of PTH1 receptor-specific, lead drug candidates for the treatment of osteoporosis.